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A Novel regulatory Role of Protein S in Blood coagulation

Protein S 在凝血中的新调节作用

基本信息

批准号：
8919831
负责人：
Rinku Majumder
金额：
$ 9.52万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8919831
关键词：
Acceleration Activated Partial Thromboplastin Time measurement Active Sites Amino Acids Anisotropy Antibodies Anticoagulants Anticoagulation Binding Binding Proteins Binding Sites Biological Assay Birth Blood Coagulation Disorders Blood Platelets Blood Vessels Blood coagulation Cardiovascular system Catalytic Domain Cells Chimera organism Coagulation Process Data Deep Vein Thrombosis Defect Development Disease Down-Regulation EGF gene Equilibrium Event Factor IX Factor IXa Factor VIIa Factor Xa Feedback Fibrin Future Generations Goals Health Hemophilia A Hemophilia B Hemorrhage Hemostatic Agents Hemostatic function Heparin Heparin Binding Heterozygote Host Defense Mechanism Human Image In Vitro Infant Infusion procedures Injury Knowledge Label Life Light Link Mass Spectrum Analysis Measurement Measures Mediating Membrane Modeling Morphologic artifacts Mus Mutate Mutation Newborn Infant Patients Phase Phospholipids Physiological Plasma Plasma Proteins Protein S Protein S Deficiency Proteins Prothrombin Pulmonary Embolism Purpura Fulminans Recombinants Regulation Reporting Risk Risk Factors Role Saphenous Vein Serine Site Specificity TFPI Testing Thrombin Thrombophilia Thrombosis Thrombus Variant Venous Thrombosis Vesicle Vitamin K Work activated Protein C base cancer procoagulant citrate carrier cofactor design fluorophore in vivo inhibitor/antagonist mouse model neutralizing antibody novel novel therapeutics prevent proband protein function research study response time use

项目摘要

DESCRIPTION (provided by applicant): A Novel Role of Protein S in Blood Coagulation Protein S (PS) is an important anticoagulant, deficiencies of which are one of several known risk factors for thrombophilia and increased risk of blood clots such as Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). In severe cases of PS deficiency, soon after birth infants develop a life-threatening blood clotting disorder called purpura fulminans. However, despite 30 years of study of this important anticoagulant, the exact function of PS is still unknown. Protein S was initially characterized as a cofactor of activated protein C (APC), but PS confers only a modest increase in APC activity. Plasma assays in the absence of APC suggested other important, APC-independent roles of PS. Some reports suggest that PS inhibits prothrombin activation to thrombin, but the validity of those reports has been questioned because of artifacts due to PS multimerization. In 2006, it was shown that PS acts as a cofactor of tissue factor pathway inhibitor (TFPI) in the initiation of coagulation. Our recent work has shown that PS inhibits factor IX (FIXa); importantly, we used conditions, e.g., high concentrations of phospholipid vesicles that avoid artifacts from PS multimers. Our goal is to mechanistically define both the physiologically relevant function of PS and the specificity of PS inhibition of FIXa. We will use a multifaceted approach to identify the regulatory role of PS. Our proposal involves detailed in vitro, ex vivo and in vivo studies to establish that protein S inhibition of FXa is specific and physiologically important. This proposal consists of two aims: 1) Determine the contact regions between FIX and PS and 2) establish the physiological significance and specificity of protein S inhibition of FIX. Successful completion of our proposal will sharply defie a novel regulatory role of PS that operates independently of APC and TFPI. The knowledge we acquire of the mechanism of this novel regulatory function will enable future development of new therapeutics designed to target the contact point between FIX and PS. Also, inhibitors of PS activity will form the basis of an adjunct therapy for hemophilia, and, by inhibiting hyper- functional FIX, PS could be used in the treatment of X-linked thrombophilia.

蛋白S （PS）是一种重要的抗凝剂，其缺乏是导致血栓形成和血栓风险增加的几个已知危险因素之一，如深静脉血栓形成（DVT）和肺栓塞（PE）。在PS严重缺乏的情况下，婴儿出生后不久就会患上一种危及生命的凝血障碍，称为暴发性紫癜。然而，尽管对这一重要抗凝剂进行了30年的研究，但PS的确切功能仍然未知。蛋白S最初被认为是活化蛋白C （APC）的辅助因子，但PS只会适度增加APC的活性。在没有APC的情况下，血浆分析提示了PS的其他重要的、不依赖于APC的作用。一些报道表明，PS抑制凝血酶原对凝血酶的激活，但这些报道的有效性受到质疑，因为PS多聚造成了伪像。2006年，研究表明，PS在凝血起始过程中作为组织因子途径抑制剂（tissue factor pathway inhibitor， TFPI）的辅助因子。我们最近的工作表明，PS抑制因子IX (FIXa)；重要的是，我们使用的条件，例如，高浓度的磷脂囊泡，避免了PS多聚体的伪影。我们的目标是从机制上定义PS的生理相关功能和PS抑制FIXa的特异性。我们将使用多方面的方法来确定PS的调节作用。我们的建议包括详细的体外、离体和体内研究，以确定蛋白S对FXa的抑制是特异性的和生理上重要的。本课题主要有两个目的：1)确定FIX与PS的接触区域；2)确定FIX对蛋白S抑制的生理意义和特异性。我们提案的成功完成将明确定义PS独立于APC和TFPI运作的新监管角色。我们获得的这种新型调节功能机制的知识将使未来开发针对FIX和PS之间接触点的新疗法成为可能。此外，PS活性抑制剂将形成血友病辅助治疗的基础，并且，通过抑制高功能FIX， PS可用于治疗x连锁血栓性病。